Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Sabatolimab is an immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on immune cells and leukaemic stem cells. In this trial, we compared the efficacy and safety of sabatolimab plus hypomethylating agent with placebo plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes. METHODS: STIMULUS-MDS1 was a multicentre, randomised, double-blind, placebo-controlled, phase 2 study done at 54 investigational sites in 17 countries. Adult patients (aged ≥18 years) with intermediate-risk, high-risk, and very high-risk myelodysplastic syndromes (according to Revised International Prognostic Scoring System criteria) who had not received previous treatment were included. Patients were randomly assigned (1:1) to intravenous sabatolimab (400 mg on day 8 and 22) or placebo plus a hypomethylating agent (intravenous decitabine 20 mg/m2 on day 1-5 or intravenous or subcutaneous azacitidine 75 mg/m2 on day 1-7 or day 1-5 and day 8 and 9) every 28 days until treatment discontinuation. The two primary endpoints were complete response rate and progression-free survival, assessed in the full analysis set, which included all randomly assigned patients. Complete response was analysed, as prespecified, 7 months after the last patient was randomly assigned. All other analyses presented, including progression-free survival, were done at the final data cutoff prespecified via a protocol amendment on Sept 2, 2021. Safety was assessed in in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03946670, and is ongoing. FINDINGS: Between July 29, 2019, and Aug 10, 2020, 127 patients were randomly assigned to sabatolimab plus a hypomethylating agent group (sabatolimab group; n=65) or placebo plus a hypomethylating agent (placebo group; n=62). The median age of participants was 73 years (IQR 69-77), of whom 86 (68%) of 127 patients were male and 77 (61%) were White. The primary endpoints were not met. Complete response (cutoff date of March 10, 2021) was achieved in 14 (22%; 95% CI 12·3-33·5) of 65 patients in the sabatolimab group vs 11 (18%; 9·2-29·5) of 62 patients in the placebo group (p=0·77). At the cutoff date of the final analysis (March 1, 2022), median follow-up for progression-free survival was 17·8 months (IQR 16·6-19·4) in the sabatolimab group and 19·2 months (17·7-22·3) in the placebo group, and the median progression-free survival was 11·1 months (95% CI 7·6-17·6) in the sabatolimab group vs 8·5 months (6·9-11·3) in the placebo group (hazard ratio 0·75 [95% CI 0·48-1·17]; p=0·1022). The most common adverse events of any grade were neutropenia (35 [56%] of 62 patients in the sabatolimab group vs 43 [68%] of 63 patients in the placebo group), thrombocytopenia (30 [48%] vs 32 [51%]), constipation (29 [47%] vs 24 [38%]), diarrhoea (27 [44%] vs 14 [22%]), anaemia (22 [35%] vs 34 [54%]), febrile neutropenia (22 [35%] vs 15 [24%]), and leukopenia (15 [24%] vs 20 [32%]). One patient developed a serious potential treatment-related immune-mediated adverse event in the sabatolimab group. There was one treatment-related death in the sabatolimab group due to pneumonitis. INTERPRETATION: The addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting. FUNDING: Novartis Pharmaceuticals.

Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study.

INTRODUCTION: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. METHODS: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%). CONCLUSION: Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.

Efetividade do aparelho de fluorescência a laser no monitoramento da desmineralização e remineralização de lesões de cárie em superfície oclusal: estudo in situ / Effectiveness of laser fluorescence device in monitoring demineralization and remineralization of occlusal caries lesions: in situ study

Introdução - O objetivo deste estudo in situ foi avaliar a efetividade do aparelho de fluorescênciaa laser (FL-DIAGNOdent) no monitoramento da des/remineralização de lesões de cárie iniciais em superfícies oclusais. Material e Métodos - Oito voluntários utilizaram um dispositivo intrabucal contendo quatro blocos de superfícies oclusais hígidas de pré-molares, sob tela para promover retenção de placa. As superfícies oclusais foram submetidas à medição com o FL. Os voluntários gotejaram solução de sacarose a 20%, oito vezes ao dia, durante 14 dias. Após esse período, foi realizada nova medição com o FL e dois blocos foram removidos dos dispositivos. Os voluntários continuaram a utilizar os aparelhos durante mais vinte e oito dias, higienizando as amostras no dispositivo sem a tela, com dentifrício fluoretado de 1100 ppm. Foi realizada a remoção dos blocos, e nova medição com FL. Todas as superfícies oclusais foram seccionadas e submetidas ao teste de dureza Knoop de seção transversal. Foi realizada ANOVA e teste de Tukey, além de teste de correlação de Pearson para os valores de dureza e do FL. Resultados - Em relação ao teste de dureza, houve diferença estatisticamente significante entre os grupos de desmineralização (261,6 ±29,9 KNHx?m) e remineralização (302,1 ± 32,2 KNHx?m, p = 0,016). Não houve diferença nos valores do FL (des:3,9 ± 2,2; re: 3,8 ± 2,0, p > 0,05) e não houve correlação significante entre as medidasdo FL e de dureza (r = ?0,145). Conclusão - Pode-se concluir que o aparelho FL não é eficaz em monitorar o processo de remineralização utilizando um estudo in situ.

Introduction - The aim of this in situ study was to evaluate the effectiveness of the laser fluorescence device (DIAGNOdent) in monitoring the demineralization and remineralization of occlusal caries surfaces. Material and Methods - Eight volunteers were selected for the study, and used an intrabucal appliance with four sterilized blocks of occlusal sound surfaces from premolar teeth.The occlusal surfaces were measured with a DIAGNOdent laser. During a period of fourteen days the volunteers drop a 20% sucrose solution on the blocks eight times a day, and used non-fluoride dentifrice. After this period, a new measurement with the DIAGNOdent was carried out and twoblocks were removed for Knoop microhardness test to verify surface demineralization. The volunteers brushed the remaining surfaces with fluoride dentifrice (1100 ppm) in the device without the plastic mesh for more twenty eight days. After this period, new measurement of the remaining surfaces in the device were carried through with DIAGNOdent. The surfaces were removed after that. All the occlusal surfaces were submitted to the Knoop cross-sectional microhardness test. Results - The effectiveness of the DIAGNOdent in monitoring the demineralization and the remineralization was evaluated. In Knoop hardness test, there was statistically significant difference between demineralization and remineralization groups (p = 0,016). There was negative correlation (r = ?0,1448) between the DIAGNOdent values and the Knoop hardness test. Conclusion - It was concluded that remineralization process was efficient in this study, although the DIAGNOdent laser can not monitor little mineral alterations.

Tratamento pulpar indireto em molar decíduo com resina composta: importância do diagnóstico e acompanhamento de três anos / Indirect pulp treatment of primary molar with composite resin: diagnosis importance and three years follow-up

O tratamento pulpar indireto é uma alternativa conservadora viável para manutenção da integridade pulpar. Entre os materiais indicados para essa técnica destacam-se o hidróxido de cálcio, por sua ação bacteriostática e bactericida e o cimento de ionômero de vidro, por sua ação antimicrobiana, adesão à estrutura dentária e liberação de flúor. O sistema adesivo é mais uma alternativa para proteção do complexo dentino-pulpar, pois proporciona um bom selamento marginal na interface dente-restauração. O objetivo deste estudo foi avaliar clínica e radiograficamente o tratamento pulpar indireto em molar decíduo com sistema adesivo e resina composta, após observação da indicação clínica. Após três anos de acompanhamento observou-se sucesso clínico eradiográfico o que faz com que essa técnica seja indicada como uma alternativa conservadora de tratamento para lesões de cárie profundas.

Indirect pulp treatment is a viable conservative alternative for keeping the integrity of the pulp. Among the indicated materials for this technique, calcium hydroxide presents bacteriostatic and bactericide action, glass ionomer presents antimicrobial capacity, adhesion dental structure and fluorid release. The adhesive system is another alternative to protect the dentin-pulp complex therefore it provides good marginal seal at the interface tooth-restoration. The aim of this study was to evaluate clinic and radiographic indirect pulp treatment in deciduous teeth with adhesive system and composite resin. After three years of surviving, the results shows clinic and radiographic success, what makes this technique indicated for a conservative alternative treatment.

Restos epiteliais de Malassez no ligamento periodontal e sua possível relação com anquilose dento-alveolar / Epithelial rests of Malassez in periodontal ligament and possible association with ankylosis

Introdução - O objetivo do presente trabalho foi investigar a presença dos restos epiteliais de Malassez e sua possível participação no processo da anquilose dento-alveolar, por meio de avaliação histológica do ligamento periodontal de dentes decíduos em infra-oclusão e retenção prolongada, com indicação de remoção cirúrgica. Material e Métodos - Foram estudados vinte e cinco dentes decíduos com diagnóstico clínico de infra-oclusão e retenção prolongada. Após exodontia os dentes foram fixados em solução formol a 10%, descalcificados em solução de ácido fórmico e citrato de sódio, processados para inclusão em parafina nos quais se realizaram cortes de 5 micrometros. Para análise morfológica, os cortes foram corados em hematoxilina e eosina e avaliados em microscopia de luz (Olympus BX60), em aumentos de 100 a 400 vezes. Resultados - Ao exame microscópico, foi possível observar a presença de restos epiteliais de Malassez no ligamento periodontal de dezesseis dentes. Observou-se também, que em área de anquilose, a presença dos restos epiteliais de Malassez promoveu interrupção localizada do processo de fusão óssea. Conclusão - Concluiu-se que os restos epiteliais presentes no ligamento periodontal podem desempenhar função inibidora do fenômeno da anquilose pela sua incompatibilidade com o tecido ósseo e pelo seu papel na manutenção do espaço do ligamento periodontal

Avaliação da inativação de lesões de cárie incipiente na dentadura decídua através de inspeção visual, fotografia e laser DIAGNOdent: estudo piloto / Evaluation of incipient caries arrestment in primary dentition by visual examination, photography, and DIAGNOdent laser: pilot study

O objetivo deste estudo foi avaliar a inativação de lesões de cárie incipiente na dentadura decídua através de inspeção visual, fotografia e laser DIAGNOdent. Foram selecionadas nove crianças, com idades entre 3 e 5 anos, que apresentavam manchas brancas ativas nos dentes decíduos anteriores superiores. As crianças selecionadas receberam orientação de higiene bucal e dieta. A seguir, foram realizadas aplicações de verniz com fluor durante cinco semanas consecutivas. A inativação das lesões de cárie foi avaliada através de três diferentes métodos: inspeção visual, fotografia e laser DIAGNOdent. Concluiu-se que houve inativação das lesões de cárie em todas as superfícies com mancha branca, uma vez que o esmalte adquiriu textura e luminosidade normais. O laser DIAGNOdent apresenta vantagens sobre os demais métodos de diagnóstico utilizados, por proporcionar valores numéricos precisos e reprodutíveis